Contemporary outcomes in IDH-mutated acute myeloid leukemia: The impact of co-occurring NPM1 mutations and venetoclax-based treatment.

Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations occur frequently in newly diagnosed (ND) acute myeloid leukemia (AML) often with co-occurring NPM1 mutations, which may influence treatment outcomes. Detailed analysis of IDH-mutated AML treated with venetoclax and influence of co-occurring NPM1 mutations remains unclear. This retrospective single-center cohort study evaluated clinical and molecular demographics,response and survival, and impact of co-occurring NPM1 mutations in patients with IDH1 or IDH2-mutated AML. 556 patients with IDH1, IDH2, and/or NPM1 mutated AML were included. Patients with IDH1 mut AML (N = 119) were more likely to have older age, sAML, ELN-adverse risk disease, and adverse-risk cytogenetics compared to those with IDH2 mut (N = 229) or IDH wt /NPM1 mut AML (N = 208). In multivariate analysis, patients with IDH2 mut (HR 0.61 [95%CI: 0.43-0.88], p value: .007) or IDH wt /NPM1 mut (HR 0.65 [95% CI: 0.45-0.94], p value: .024) AML had a decreased risk of death versus IDH1 mut AML. Venetoclax-based lower-intensity regimens partially abrogated the detrimental effect of IDH1 mut with similar OS observed between IDH1 mut /NPM1 wt , IDH2 mut /NPM1 wt , and IDH wt /NPM1 mut AML. With regards to the influence of IDH mut /NPM1 mut cases, IC improved survival in IDH2 mut /NPM1 mut versus IDH2 mut /NPM1 wt AML (HR: 0.54 [95% CI: 0.2644-1.082], p value: .077), while venetoclax-based therapy improved survival in IDH1 mut /NPM1 mut versus IDH1 mut /NPM1 wt AML (HR: 0.094 [95% CI: 0.01-0.74], p value: .0056). Differing outcomes were observed in IDH1 mut versus IDH2 mut or NPM1 mut AML which were influenced by co-occurring NPM1 mutations and partially abrogated with venetoclax-based therapy. Given the differing biology and survival in IDH1 mut AML, investigations incorporating molecularly targeted therapies such as IDH inhibitors remain warranted in this subgroup.